1. Field of the Invention (Technical Field)
The present invention relates to linear peptides with a C-terminus —OH group that are specific for one or more melanocortin receptors, and which may be used in the treatment of melanocortin receptor-mediated disorders, including a variety of body weight disorders such as cachexia, for treatment of inflammation and immune disorders, and other conditions and diseases.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates or priority claims certain publications or patent applications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications and applications herein is given for more complete background and is not to be construed as an admission that such publications or applications are prior art for patentability determination purposes.
A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues.
Significant work has been done in determining the structure of melanocortin receptors, including both the nucleic acid sequences encoding for the receptors and the amino acid sequences constituting the receptors. See, for example, International Patent Application Nos. PCT/US98/12098 and PCT/US99/16862 and U.S. Pat. No. 5,994,087. MC4-R is a G protein-coupled, 7-transmembrane receptor that is believed to be expressed primarily in the brain. Inactivation of this receptor by gene targeting has been reported to result in mice with the maturity-onset obesity syndrome that is associated with hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar D, Lynch C A, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141, 1997). MC4-R is a molecular target for therapeutic intervention in energy homeostasis.
A large number of ligands specific for melanocortin receptors, both agonists and antagonists, have been developed. See, for example, International Publication No. WO 01/13112 and U.S. Publication No. 2005/0164914 (metallopeptides specific for MC receptors); U.S. Pat. No. 6,054,556 (cyclic lactam peptides as MC1-R, MC3-R, MC4-R and MC5-R antagonists); U.S. Publication No. 2004/0138136 (cyclic peptides for treatment of sexual dysfunction); U.S. Publication No. 2005/0038230 (linear and cyclic melanocortin receptor-specific peptides); International Publication No. WO 2005/014617 (C-terminus —OH group cyclic peptides); U.S. Publication Nos. 2006/0014676 and 2006/0014194 (cyclic peptides for treatment of cachexia including one or more NaI amino acid residues); International Publication No. WO 2005/030797 (cyclic peptides optionally including a NaI amino acid residue); and U.S. Publication No. 2005/0239711 (MC4-R agonist linear peptides). In addition, a large number of patents teach various methods of screening and determining melanocortin receptor-specific compounds, as for example U.S. Pat. Nos. 5,932,779 and 5,994,087.
In general, compounds specific for MC3-R, MC4-R or MC5-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of cachexia, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and other treatment of other food intake and metabolism-related purposes. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used to regulate blood pressure, heart rate and other neurophysiologic parameters. MC4-R antagonists can be employed to alleviate numerous conditions such as anxiety/depression, pain, and addiction to drugs of abuse. In at least one report, MC4-R agonists are described as useful to inhibit or reduce voluntary alcohol consumption (International Publication No. WO 2005/060985).
Body weight disorders can include one or more “wasting” disorders (e.g., wasting syndrome, cachexia, sarcopenia) which cause undesirable and/or unhealthy loss of weight or loss of body cell mass. In the elderly as well as in cancer and AIDS patients, wasting disease can result in undesired loss of body weight, including both the fat and the fat-free compartments. Wasting diseases can be the result of inadequate intake of food and/or metabolic changes related to illness and/or the aging process. Cancer patients and AIDS patients, as well as patients following extensive surgery or having chronic infections, immunologic diseases, hyperthyroidism, extraintestinal Crohn's disease, psychogenic disease, chronic heart failure or other severe trauma, frequently suffer from wasting disease which is sometimes also referred to as cachexia, a metabolic and, sometimes, an eating disorder. Cachexia is additionally characterized by hypermetabolism and hypercatabolism. Although cachexia and wasting disease are frequently used interchangeably to refer to wasting conditions, there is at least one body of research which differentiates cachexia from wasting syndrome as a loss of fat-free mass, and particularly, body cell mass (Mayer, J. Nutr. 129(1S Suppl.): 256S-259S, 1999). Sarcopenia, yet another such disorder which can affect the aging individual, is typically characterized by loss of muscle mass. End stage wasting disease as described above can develop in individuals suffering from either cachexia or sarcopenia. Certain patents teach the use of melanocortin antagonists for treatment of cachexia and other weight-related disorders. See, for example, U.S. Pat. Nos. 6,716,810; 6,699,873; 6,693,165; 6,613,874; 6,476,187; 6,284,729; 6,100,048; and 5,908,609. However, none of these disclose the peptides of the present invention.
The cyclic peptide SHU9119 (Ac-Nle-cyclo(-Asp-His-D-NaI 2-Arg-Trp-Lys)-NH2) is disclosed in U.S. Pat. No. 5,731,408. Related cyclic peptides are disclosed in U.S. Pat. No. 6,054,556. U.S. Publication No. 2003/0113263 discloses a method for characterizing a compound useful for treating an animal with cachexia, including use of an MC4-R antagonist to treat an animal with cachexia, and specifically disclosing SHU9119. U.S. Publication No. 2003/0105024 discloses SHU9119 as a MC receptor antagonist used experimentally to stimulate feeding behavior. U.S. Pat. No. 6,476,187 similarly discloses SHU9119 as a MC receptor antagonist used experimentally to stimulate feeding behavior. U.S. Publication No. 2003/0032791 discloses the experimental use of SHU9119 in various assays. U.S. Publication No. 2002/0016291 discloses SHU9119 as an antagonist at the MC3 and MC4 receptors. In 1997, it was disclosed that SHU9119 enhanced feeding behavior. Fan, Boston, Kester, Hruby, Cone: Nature 385:165-168, 1997; see also Endrocrinology, 139:4428-31, 1998; Endrocrinology, 142:3292-3301, 2001; and Cancer Research, 61:1432-1438, 2001.
There remains a significant need for peptides with high specificity for discrete melanocortin receptors, as well as peptides that are either antagonists or inverse agonists of specific melanocortin receptors. High affinity peptide ligands of melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as antagonists or inverse agonists. In one aspect, antagonists or inverse agonists of MC4-R can be used to treat eating disorders or cachexia. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity peptide ligands of melanocortin receptors can be used to regulate cytokine activity. Thus such peptides may further be used for treatment of inflammation and other immune disorders. In another aspect, MC4-R specific peptides can be used to treat anxiety/depression, pain, and addiction to drugs of abuse, including inhibition or reduction of alcohol consumption.